1. Field of the Invention
The invention relates to processes for substitution of aromatic organic compounds. More specifically, the invention relates to processes for the introduction of alkoxy substituents or what may broadly be regarded as "alkoxy-type" substituents in replacement for halogen substituents upon an aromatic nucleus; and to catalytic materials employed therein.
2. Description of the Prior Art
The simplest of alkoxy substituents is the methoxy group, which is moreover probably the one most commonly encountered, occurring with remarkable frequency in the structures of biologically-active compounds. There are numerous existing commercial syntheses, and many more potentially-important syntheses, in which it is necessary either directly or indirectly to introduce an alkoxy substituent, usually a methoxy group, or some kind of alkoxy-type substituent into an aromatic ring system. Indirect routes by their nature tend to be economically less attractive than direct ones where an alkoxy residue substitutes directly into the aromatic ring. Such reactions have been known for some time, but activation of the ring by electron withdrawing groups such as nitro-groups was usually necessary for efficient conversion.
Copper catalysis [Pepper et al., Can. J. Chem., 31, 476-483 (1953)] was little used until the late 1950's, and such reactions, especially the Ullmann reaction, although of more general application, tended to proceed only under forcing conditions, i.e., high temperatures (180.degree.-250.degree. C.) and costly solvents such as quinoline or substituted pyridines, and yields were often low. Because copper powder was usually employed, reproducibility was often poor since the catalysis is in fact homogeneous and the physical state of the copper powder varied in its activity.
Work in the early 1960's [Bacon et al., Proc. Chem. Soc., 113-114 (1962); Bacon et al. J. Chem. Soc., 1097-1119 (1964)] clarified the application of copper catalysts in aromatic substitution and paved the way to a series of publications on synthetic applications. It was shown that cuprous salts were far more active catalysts, especially when solubilized by suitable solvents, especially aprotic dipolar ones such as dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). These solvents lowered the temperature at which reasonable reaction rates were achieved from about 180.degree.-200.degree. C. to 130.degree.-160.degree. C. It was also shown that cuprous oxide tended to favor reduction, especially in the presence of suitable hydride donors, and in fact reduction was often a competing reaction, especially in certain solvents [Bacon et al., (1964) supra; Bacon et al., J. Chem. Soc. C, 308-315 (1969)].
By the mid-1970's, the chemistry of copper catalysed aromatic substitution could be summarized as follows. Various nucleophiles [Bacon et al., (1969) supra; Bacon et al., J. Chem. Soc. C, 1978-1981 (1969)], e.g., halides [Hardy et al., J. Amer. Chem. Soc., 80, 1716-1718 (1958)], cyanides [Newman et al., J. Org. Chem., 2525 (1961)], phenoxides [Bacon et al., (1964) supra], thiophenoxides [Adams et al., J. Amer. Chem. Soc., 81, 4927-4931 (1959)], hydroxide [British Pat. No. 1,338,890 (Nov. 28, 1973)], and alkoxides [Pepper et al., (1953) supra; U.S. Pat. No. 4,102,933 (July 25, 1978); McKillop et al., Syn. Comms., 35-43 (1974); Litvak et al., Zh. Org. Khim., 10, 2373-2376 (1974)] would displace the halide, usually bromide, in aromatic halides in the presence of catalytic quantities (20-50 molar %) of copper(I) ion salts at moderate temperatures (130.degree.-170.degree. C.) in high boiling bases such as .alpha.-picoline [Hardy et al., (1958) supra] and 2,4,6-collidine [Bacon et al., J. Chem. Soc., 1978-1981 (1969)], or dipolar aprotic solvents such as DMF [McKillop et al., (1974) supra], N-methylpyrrolidone [Newman et al., (1961) supra] and DMSO [Bacon et al., (1964) supra]. Yields were good but reaction times were, in general, long. In special cases these reactions were sufficiently good to be of economic interest [British Pat. No. 1,338,890].
Litvak et al., (1974) supra, Torii et al., J. Org. Chem., 44, 3305-3310 (1979) and U.S. Pat. No. 4,218,567 (Aug. 19, 1980) disclose that, in specific cases, good yields can be achieved in the copper catalyzed substitution of a methoxy substituent for aromatic bromide under somewhat milder conditions, but nevertheless still in expensive solvents (DMF, pyridine).